Field of the Invention
The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to the treatment of neoplastic diseases, such as cancer.
Description of the Related Art
Cancer is a leading cause of death in the United States. Despite significant efforts to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination. Surgery and radiation therapy, however, are generally useful only for fairly defined types of cancer, and are of limited use for treating patients with disseminated disease. Chemotherapy is the method that is generally useful in treating patients with metastatic cancer or diffuse cancers such as leukemias. Although chemotherapy can provide a therapeutic benefit, it often fails to result in cure of the disease due to the patient's cancer cells becoming resistant to the chemotherapeutic agent.
Therefore, a need exists for additional chemotherapeutics to treat cancer. A continuing effort is being made by individual investigators, academia and companies to identify new, potentially useful chemotherapeutic and anti-microbial agents.
The successful development of Bortezomib/PS-341 therapy for treatment of relapsed/refractory multiple myeloma (MM) has established proteasome inhibition as an effective therapeutic strategy. The dipeptide boronic acid analogue Bortezomib is a potent, highly selective, and reversible proteasome inhibitor which targets the 26S proteasome complex and inhibits its function. The 26S proteasome is an adenosine triphosphate (ATP)-dependent multicatalytic protease mediating intracellular protein degradation. Proteasomal degradation of misfolded or damaged proteins proceeds by recognition of polyubiquitinated proteins by the 19S regulatory subunit of the 26S protease, and subsequent hydrolysis to small polypeptides. Bortezomib primarily inhibits chymotryptic, without altering tryptic or caspase-like, proteasome activity. Besides inhibiting NF-kB, Bortezomib has pleiotropic effects on MM biology by targeting: 1) cell-cycle regulatory proteins; 2) UPR pathway via modulating transcriptional activity of plasma cell differentiation factor X-box binding protein-1 (XBP-1); 3) p53-mediated apoptosis/MDM2; 4) DNA repair mechanisms; 5) classical stress-response pathways via both intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) cell death cascades. Specifically, Bortezomib activates JNK, which triggers mitochondrial apoptotic signaling: release of cytochrome-c (cyto-c) and second mitochondrial activator of caspases (Smac) from mitochondria to cytosol, followed by activation of caspase-9 and caspase-3. However, both intrinsic and acquired resistance has already been observed, and there are no therapies to overcome Bortezomib resistance at present.